过硫酸钠氧化鬼臼毒素及其衍生物的机理研究

用激光光解和脉冲辐解技术对过硫酸钠氧化鬼臼毒素及其衍生物水溶液的机理进行了研究。观察了各种瞬态粒子的生成和衰变过程,并测定了各种瞬态粒子的生成和衰变速率常数,发现鬼臼毒素的C-4位,去甲表鬼臼毒素的C-4位和C-1基团的C-4′位都是很活泼的基团,具有强光敏性,并分析其反应机理和分子结构的关系。     

鬼臼毒素及VP-16化学活性的激光光解与脉冲辐解研究

运用激光光解与脉冲辐解技术, 对用于肿瘤治疗的鬼臼毒素(PPT)和依托泊甙(VP-16)的化学活性进行了详细的研究. 结果表明: 鬼臼毒素及VP-16经248 nm的激光激发可光电离, 且光电离的量子产额比较高, 有很强的光敏性, 而且还有多个活性基团分别与水合电子、氢原子、羟基自由基作用生成不同的瞬态粒子, 并推断出相应的反应机理. 为医学工作者进一步了解、利用鬼臼毒素和VP-16, 探讨其抗肿瘤机理提供科学的参考, 也为化学工作者进一步合成高效、低毒的抗肿瘤药物提供新思路.     

含冠醚结构单元吲哚啉螺苯并吡喃的时间分辨光谱

采用纳秒激光光解技术研究了含冠醚螺吡喃化合物（简称ＢＮ－ＢＩＰＳ）的光致变色过程．结果表明：ＢＮ－ＢＩＰＳ是经一激发单线态生成醌式结构的部花菁Ｂ；在乙腈溶液中，激发生成的部花菁Ｂ的瞬态吸收有较明显的衰减，同时４４０ ｎｍ左右有新的瞬态吸收生成；当在ＢＮ－ＢＩＰＳ的乙腈溶液中加入高氯酸钠后，激发生成的部花菁Ｂ的瞬态吸收衰减加快， ４４０ ｎｍ左右的瞬态吸收生成也同步加快．但在ＢＮ－ＢＩＰＳ相对应的不含冠醚的螺吡喃ＢＩＰＳ中，未观察到异构体Ｃ的生成．     

水相中四氯化碳的激光闪光光解研究

利用激光闪光光解技术研究了水相中四氯化碳光分解和光氧化的微观机制,并且指证了水相中四氯化碳受光激发所产生的瞬态光谱中的一些瞬态物种的特征吸收峰。并对这些瞬态物种的行为和归宿进行了研究。研究表明在248nm激光作用下,四氯化碳受光激发将分解为CCl~3^.自由基和Cl^.自由基。CCl~3^.自由基在无氧/有氧条件下的反应途径是不同的:在无氧条件下CCl~3^.自由基将进行偶合反应生成更难于降解的C~2Cl~6;而在有氧条件下CCl~3^.自由基则与O~2反应生成CCl~3O~2^.自由基,而CCl~3O~2^.自由基最终转变为COCl~2,这意味着光氧化能够有效地降解CCl~4。Cl^.自由基基本上不受氧气存在的影响,其归宿是与水分子发生电荷转移反应。     

水相中·OH, ·H和e-aq与2-氯酚反应机理研究

利用脉冲电子束辐解水产生*OH自由基、 *H及水合电子(e-aq), 研究了这些活性粒子在多种条件下与水相中2-氯酚的微观反应机理, 对其瞬态光谱中的主要吸收峰做了归属, 并初步考察了这些瞬态物种的生长、衰减等行为. 研究表明, *OH自由基与2-氯酚在碱性条件下可直接反应生成邻氯代酚氧自由基, 速率常数为1.0×109 L*mol-1*s-1, 也有部分*OH自由基与2-氯酚反应先生成OH-加合物, 再进一步消除水分子生成邻氯代酚氧基; 在酸性条件下要经过OH-加合物. *H则与2-氯酚反应生成H-加合物; e-aq可直接从2-氯酚分子夺氯, 在近中性和碱性环境中, 该反应的速率常数分别为1.25×109 L*mol-1*s-1和6.3×108 L*mol-1*s-1.     

新一类抗肿瘤药物N-糖苷类化合物的光化学活性

N-糖苷类化合物以其无毒和高效抗肿瘤活性而成为当今研究的热点．本研究应用时间分辨激光光解技术,详细研究了N-（α-D-吡喃型葡萄糖苷）水杨酰肼（N-（α-D—glucopyranoside）salicyloyl hydrazine,NGSH）在激光脉冲的作用下所产生的各种瞬态物种的行为．结果表明,在266nm的激光作用下,NGSH可发生单光子电离,其量子产率为0．02,光致电离效率较高,在细胞的含氧体系中,水合电子很容易跟O2结合生成超氧阴离子自由基和单线态氧,这二者是杀灭肿瘤细胞最强的活性物质．NGSH光电离产生的阳离子自由基可以脱去质子生成中性自由基,其pKa4．02,NGSH^＋的衰减速率常数为2．55×10^9dm^3·mol^-1·S^-1．用SO4ˉ自由基氧化NGSH,得到NGSH^＋的生成速率常数为k=1．76×10^-9 dm3·mol^-1·S^-1,进一步验证了光电离结果．     

CS2与亚硝酸水溶液复相体系的激光闪光光解

利用激光光解-瞬态吸收技术研究了氮气饱和条件下CS2与亚硝酸水溶液复相体系的355nm光解机理.瞬态吸收光谱分析结果表明:CS2与·OH自由基快反应生成CS2OH,产生的CS2OH继续与HONO反应生成CS2OH-HONO加合物,其吸收峰分别为285,305,475,490和980nm,反应CS2OH+HONOCS2OH-HONO的二级速率常数为(2.79±0.05)×108L/(mol·s);230nm处的吸收峰归属为CS2NO+,其一级衰减速率常数为1.28×105s-1.     

利用瞬态吸收光谱技术研究水体中苯与亚硝酸的交叉反应机理

利用瞬态吸收光谱技术进行了有氧、无氧条件下苯与亚硝酸水溶液复相体系的交叉反应机理研究 ,初步考察了这些瞬态物种的生长与衰减等行为 ;并对其光解产物进行了GC/MS分析 .研究表明 ,HNO2 在 3 5 5nm紫外光的照射下可产生·OH和NO+ ,·OH自由基和苯反应生成C6H6 OHadduct ,反应速率常数为 8 9× 10 9L·mol-1·s-1,在有氧条件下C6H6 OHadduct进一步氧化为C6H6 OHO2 ,反应速率常数 3 3× 10 8L·mol-1·s-1;NO+ 自由基和苯作用形成C6H6 NO+ πcomplex ,然后进一步分解     

新颖瞬态物种的产生与表征

基于对紫外光电子能谱(PES)仪的不断改进, 成功地生成与表征了系列新颖瞬态物种. 简要综述了PES的基本原理; 系列新颖瞬态物种活性卤素化合物、短寿命自由基、亚稳态拟卤素化合物的PES实验和理论量子化学研究; 以及新建立的紫外光电子能谱与HeI光光电离飞行时间质谱联合谱仪(PES/HeI-TOFMS)在瞬态物种的研究进展. 而PES/HeI-TOFMS联合谱仪的建立使得PES在复杂化学过程以及瞬态物种的捕获与表征研究中发挥更大的作用.     

在KBr、KI、KCNS水溶液的脉冲辐照中观察到的瞬态吸收光谱

利用自行研制的微秒级脉冲辐解实验装置,在KBr,KI 和KCNS水溶液的脉冲辐解中观察到了Br_2~-·I_2~-·和(CNS)_2~-阴离子自由基的瞬态吸收光谱。这些阴离子自由基的形成都和水辐解的初级产物OH自由基有密切联系。本文简要介绍了脉冲辐解实验装置,对上述三种阴离子自由基的形成及衰减动力学进行了简单讨论。     

The mechanism of photo-ionization of podophyllotoxin and its derivatives:: a laser flash photolysis study

Podophyllotoxin and its derivatives are very light (UV) sensitive, and can be readily photo-ionized to produce some transient species, such as radical cation, radical anion and superoxide anion radical. The laser flash photolysis of podophyllotoxin and its derivatives has been performed for the first time. The mechanism of photo-ionization has been confirmed and illustrated. In addition, the related reaction rate constants and molar extinction coefficients of the transient species have been determined.     

Laser flash photolysis and pulse radiolysis study on chemical activity of VP-16 and podophyllotoxin

Time-resolved laser flash photolysis and pulse radiolysis have been used to study the chemical activity of podophyllotoxin(PPT) and etoposide(VP-16). The mechanism of photoioniza-tion of etoposide and podophyllotoxin has been confirmed and illustrated. It is demonstrated that VP-16 and PPT in aqueous solution can be photoionized at 248 nm to give hydrated electron and neutral radical resulting from rapid deprotonation of radical cation of VP-16 and PPT. The quantum yield for the photoionization of VP-16 and PPT with single-photo is 0.21 and 0.61, respectively. In addition, they can react with hydrated electron, hydrogen radical and hydroxyl radical. This will give chemists some advice on synthesizing new derivatives of podophyllotoxin in cancer treatment.     

Oxidizing mechanism of podophyllotoxin and its derivatives by sodium persulfate

The oxidizing mechanism of podophyllotoxin and its derivatives by sodium persulfate has been studied by laser flash photolysis and pulse radiolysis. The formation and decay processes of transient species of podophyllotoxin and its derivatives have been observed, and a series of rate constants for the formation and decay of transient species have been determined. It has been found that there is a light (UV) sensitive group on the C-4 of podophyllotoxin and two light (UV) sensitive groups on the C-4 and C-4' of 4'-demethylepipodophyllotoxin.     

The intramolecular carboxyarylation approach to podophyllotoxin

Since 1960, only seven plant-derived anticancer drugs have received FDA approval for commercial production. Two are semisynthetic derivatives of podophyllotoxin. This paper describes concise, highly convergent, and conceptually novel approaches to (-)-podophyllotoxin and its enantiomer. These highly convergent syntheses feature a late-stage domino radical reaction to install the lactone ring and the pendant trimethoxyphenyl group.     

Design, synthesis, and biological evaluation of novel spin-labeled derivatives of podophyllotoxin as potential antineoplastic agents. Part XII

Five novel nitroxyl spin-labeled ester derivatives of podophyllotoxin (11a-11e) have been prepared and their structural information on these nitroxyl spin-labeled ester derivatives of podophyllotoxin (11a-11e) using (1)HNMR spectroscopy was efficiently obtained by application of the in situ reduction of representative nitroxyl spin-labeled ester derivative of podophyllotoxin 11e with phenylhydrazine for the preparation of N-hydroxylamine 12 in the NMR tube. These novel derivatives were further evaluated for their in vitro cytotoxic activity against five neoplastic cell lines (K562, HL-60, SPCA-1, Lewis, and L-1210) using MTT assay. Most of the target compounds (except for all these compounds against SPCA-1) exhibited more pronounced cytotoxicity against several neoplastic cell lines than that of the prototypical inhibitor etoposide.     

Tuned C?H Functionalization to Construct Aza‐Podophyllotoxin/Aza‐Conidendrin Derivatives by Means of Domino Cyclization

An efficient domino cyclization method for the construction of aza‐podophyllotoxin/aza‐conidendrin derivatives has been established. Reactions of different dienes with aryl halides in the presence of a palladium catalytic system produced different kinds of podophyllotoxin derivatives through a highly regioselective C? H functionalization. Treatment of dienes with aryl halides that have electron‐withdrawing substituents on the phenyl ring created aza‐podophyllotoxin derivatives by means of the functionalization of the C? H bonds ortho to the C? halide bonds of the incoming aryl halides. The reaction of dienes with 1‐iodobenzene or aryl halides that incorporate electron‐donating groups produced aza‐conidendrin derivatives by means of the functionalization of both sp³ C? H and sp² C? H bonds. The regioselective C? H functionalization for the formation of different pseudo‐podophyllotoxin/‐conidendrin derivatives is proven by analyses of the ¹H NMR spectra of the products and selective X‐ray analyses of the structures of the products. Thus, the palladium‐catalyzed domino cyclization of 1,6‐dienes for the preparation of aza‐podophyllotoxin/aza‐conidendrin derivatives can be controlled by selectively controlling the C? H functionalization.     

鬼臼毒素及其衍生物的单电子还原电位测定

采用脉冲辐解技术,杜醌作参比物,通过改变鬼臼毒素、去甲表鬼臼毒素和VP-16的浓度,控制其阴离子向杜醌电子转移的速度,测得了鬼臼毒素、去甲表鬼臼毒素和VP-16的单电子还原电位分别为-310,-339和-334mV,揭示了鬼臼毒素及其衍生物作为抗肿瘤药物的辐射增敏机理.     

Design, synthesis and cytotoxicity of novel podophyllotoxin derivatives

A series of novel podophyllotoxin derivatives were designed using association strategy and synthesized by coupling either podophyllotoxin (1) or 4beta-amino podophyllotoxin (3) with substituted indol-3-yl-glyoxyl chlorides. Their structures were identified using spectroscopic techniques. These novel derivatives have been evaluated for cytotoxicity in vitro against four human cancer cell lines with comparison to the parent compounds 1, 3 and indibulin (2). Some of the compounds (7a, 7c) showed comparable cytotoxicity to that of podophyllotoxin.     

Synthesis and insecticidal activities of novel derivatives of podophyllotoxin

In order to find the biorational pesticides, eight novel 4beta-substituted phenoxyaniline derivatives of podophyllotoxin (4a-h) have been synthesized with significant stereoselectivity and improved yields by employing the BF(3).Et(2)O/NaI reagent system and evaluated for insecticidal activity against Pieris rapae as well as for their antifeedant effect against fifth instar larvae of P. rapae. The results showed that all these derivatives of PPT showed delayed insecticidal activity, which is different from the traditional neurotoxic insecticides. Among them, compounds possessing a 4beta-phenoxyaniline moiety substituted at para (CO(2)C(2)H(5), Cl, and OH) position exhibited greater insecticidal activity against P. rapae than podophyllotoxin. Also, the antifeedant activities showed that these compounds exhibited less potency than podophyllotoxin.     

Design,Synthesis and Antitubulin Activity of Novel Podophyllotoxin Derivatives as Potent Anticancer Agent

Twenty novel podophyllotoxin derivatives(1―20) were designed and synthesized. The anti-proliferation activities of these compounds were evaluated against three human cancer cell lines(HepG2, Calu-1 and MCF-7) using podophyllotoxin and Combretastatin A4(CA-4) as positive controls. Among all the compounds, compound 2 displayed more significant anti-proliferation activities against MCF-7 and Calu-1 cell lines and showed lower toxicity towards non-cancer cells. Furthermore, the cell cycle and apoptosis analysis results revealed that compound 2 can cause cell arrest at G2/M phase, leading to cancer cell apoptosis. Meanwhile, it can also reduce the adhesive ability of Calu-1 cells to fibronectin and laminin. The docking simulation results demonstrated that compound 10 can nicely bind to the colchicine site of tubulin. The podophyllotoxin derivatives are worthy to be further investigated to obtain more potent anti-cancer drugs.